The term, hypereosinophilic syndromes (HES), refers a spectrum of patients with elevated blood eosinophils. Over the past two decades, certain categories of patients have been recognized as HES subgroups. For example, the syndromes of episodic angioedema associated with eosinophilia, the syndrome of nodules, eosinophilia, rheumatism, dermatitis and swelling, HES associated with T cell clones, and the myeloproliferative variant have been recognized. Patients with T cell clones producing TH2 cytokines show evidence of L-5 production and IL-5 stimulates bone marrow production and activation of eosinophils. Mepolizumab is a high-affinity, specific, humanized monoclonal antibody to IL-5 which rapidly depletes eosinophils from the peripheral blood. This antibody has been administered to patients with several diseases, including asthma, and it is remarkably free of side-effects. The accompanying core clinical protocol describes a trial of mepolizumab for the treatment of HES; this mechanistic proposal seeks to understand the basic mechanisms underlying the response to mepolizumab. Specifically, we will: 1. Determine whether mepolizumab modulates T-cell functions, including their differentiation and cytokine production. 2. Test whether mepolizumab treatment suppresses eosinophil activation, cytokine production and expression of the IL-5 receptor on the eosinophils of treated patients. 3. Determine whether mepolizumab reveals heterogeneity in HES not heretofore recognized. Overall, this is a unique and unprecedented opportunity to conduct a multicenter study involving investigators with considerable experience to investigate the effects of anti-IL-5 administration and to determine which markers of eosinophil activation are best correlated with disease activity. Previous studies have largely been from single institutions, and this will be the first multicenter study. We anticipate the results will shed new light on this disease by defining essentially all HES subtypes and their frequencies, by determining the ability of anti-IL-5 to alter the immunological bases of HES, by identifying and investigating patients not responsive to anti-IL-5 and by identifying the characteristics of patients who can be effectively treated with anti-IL-5. [unreadable] [unreadable] [unreadable] [unreadable]